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Steady progress

New ARV classes can slow drug resistance in HIV patients diagnosed in pre-HAART era

Human immunodeficiency virus (HIV) is a retrovirus that, in infected hosts, can lead to the development of acquired immunodeficiency syndrome (AIDS). With AIDS, the immune system starts to shut down, affording other infections the opportunity to become life-threatening.

HIV infection is now pandemic. In 2006, the number of new HIV infections rose to 4.3 million, resulting in a total of 39.5 million people infected. This was an increase of 2.6 million compared with 2004. A total of 2.9 million people died as a result of AIDS-related illnesses in 2006. Almost three quarters of these deaths occurred in sub-Saharan Africa.

Treatment of HIV generally consists of a combination of three or more antiretroviral agents, commonly known as highly active antiretroviral therapy (HAART). As of June 2007, 22 compounds had been formally approved by the US Food and Drug Administration (FDA) for the treatment of HIV infections. These can be sorted into five classes: nucleoside reverse transcriptase inhibitors (NRTIs) eg, zidovudine; nucleotide reverse transcriptase inhibitors (NtRTIs) eg, tenofovir disoproxil fumarate; non-nucleoside reverse transcriptase inhibitors (NNRTIs) eg, nevirapine; HIV protease inhibitors (PIs) eg, lopinavir and fusion inhibitors (FIs) eg, enfuvirtide.

While there are, as yet, no vaccines or cures for HIV, new antiretroviral drugs are constantly under development, including two new drug classes: HIV integrase inhibitors and chemokine (C-C motif) receptor 5 (CCR5) antagonists.

HIV integrase inhibitors
HIV integrase inhibitors inhibit the integration of a DNA copy of the RNA genome into the host cell chromosome, a vital step in retroviral replication. Several HIV integrase inhibitors, including the first in the class, raltegravir (Isentress), are showing promise in HIV-infected patients with no or limited other treatment options.

Raltegravir, developed by Merck & Co, is currently in pre-registration in the US and is in phase III trials in Asia, Australia, Central America, Europe and South America.

Interim results from two large phase III studies (BENCHMRK-1 and -2) have demonstrated that raltegravir, at dosages of 800 mg/day, is associated with significant antiretroviral activity when combined with optimised background therapy (OBT) in patients with triple-class resistant HIV-1 infections. After 16 weeks of treatment, significantly more raltegravir recipients (77 per cent in both studies) than placebo recipients (41 per cent in BENCHMRK-1 and 43 per cent in BENCHMRK-2) achieved viral loads of <400 copies/mL; similar proportions achieved <50 copies/mL (raltegravir 61 per cent and 62 per cent versus placebo 33 per cent and 36 per cent, respectively).

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In September 2007, the Antiviral Drugs Advisory Committee of the FDA voted unanimously to recommend accelerated FDA approval of raltegravir.

Gilead Sciences and Japan Tobacco's elvitegravir is another HIV integrase inhibitor, which is currently in phase II development. After 24 weeks of treatment, elvitegravir + OBT (consisting of NRTIs with or without enfuvirtide) was significantly superior to protease inhibitors + OBT (-1.7 log10 copies/mL vs -1.2 log10 copies/mL) in the reduction of HIV viral load, particularly among those patients who were receiving enfuvirtide for the first time.

However, to maintain these results, an active optimised background regimen is critical because, within 24 weeks of the initial sharp drop in viral load with HIV integrase inhibitor therapy, virus levels had rebounded - almost to baseline - among patients without an active drug in their OBT. The net drop among these patients was 0.7 log10 copies/mL.

Other HIV integrase inhibitors, currently in phase I development, include C 2507 (Merck) and GS 9160 (Gilead Sciences).

CC5 antagonists
HIV enters T cells by binding to the CD4 receptor and either CCR5 or chemokine (C-X-C motif) receptor 4 (CXCR4). CCR5 antagonists block cellular entry by the HIV strain known as R5 tropic virus, which binds exclusively to CCR5 and is the sole strain detectable in over 85 per cent of patients beginning HIV therapy and 50-60 per cent of highly treatment-experienced patients.

Pfizer developed maraviroc (Selzentry, Celsentri), a first-in-class CCR5 antagonist that was recently launched in the US, is in pre-registration in the EU, and is in clinical development worldwide. Maraviroc has also been granted priority review in Canada. In preclinical studies, maraviroc demonstrated cross-clade potency against CCR5 isolates.

Two phase IIb/III trials (MOTIVATE-1 and -2) were conducted in over 1,000 treatment-experienced patients with HIV-1. Patients in MOTIVATE-1 were randomised to treatment with maraviroc once or twice daily, or placebo, each combined with OBT. After 24 weeks, the addition of maraviroc significantly improved viral control and increased CD4 cell count compared with placebo.

A total of 42 per cent and 49 per cent versus 25 per cent of patients receiving maraviroc once daily, maraviroc twice daily or placebo, respectively, achieved a viral load of <50 copies/mL HIV RNA. Recent data indicate that this response was continued for a further 24 weeks.

Patients in MOTIVATE-2 were randomised to treatment with placebo or lower doses of maraviroc than in MOTIVATE-1, each combined with OBT. After 24 weeks, 41 per cent, 46 per cent and 21 per cent of patients receiving maraviroc once or twice daily or placebo, respectively, achieved a viral load of <50 copies/mL HIV RNA.

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There was a significant mean decrease in viral load, and a significant mean increase in CD4 cell count, among maraviroc recipients compared with placebo. Maraviroc, in combination with other antiretrovirals, is indicated for treatment-experienced adult patients infected with only CCR5-tropic HIV-1, who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.

Currently undergoing phase III development by Schering-Plough, vicriviroc has also demonstrated antiviral potency against a panel of CCR5 tropic HIV genotypes. Vicriviroc is in two multicentre phase III clinical trials (VICTOR-E3 and -E4), which are anticipated to enrol approximately 375 patients each. In a phase II study, treatment-experienced patients with HIV-1 were randomised to treatment with placebo or vicriviroc 5, 10 or 15 mg/day, in addition to OBT. At 48 weeks, a greater proportion of patients in the 10 and 15 mg/day vicriviroc groups than in the placebo group had achieved a viral load of <50 copies/mL HIV RNA (37 per cent and 27 per cent versus 11 per cent, respectively). The FDA has granted vicriviroc fast-track status.

A third CCR5 antagonist, PRO 140, under development by Progenics Pharmaceuticals, has received some attention recently. In a phase Ib trial of 0.5, 2 or 5 mg/kg dosages, in patients who had not taken any antiretroviral therapy within the past three months and who had HIV plasma concentrations of ?5000 copies/mL, a single 5 mg/kg intravenous dose of PRO 140 led to a reduction in HIV-1 RNA levels by an average of 1.7 log10 after 10 days. The response rate was dose-dependent, with 100 per cent of 5 mg/kg recipients responding to treatment.

Other CCR5 antagonists currently in earlier stages of development include INCB 9471 (Incyte Corporation), ancriviroc (Schering-Plough), INCB 15050 (Incyte Corporation), TAK 652 (Takeda) and TAK 220 (Takeda).

These new classes, in combination with other antiretrovirals, may slow the development of drug resistance. They appear to have particular potential in patients who developed HIV positivity in the pre-HAART era, and who may be at greater risk of treatment failure due to resistance caused by the then accepted administration of mono- or dual therapy regimens.

Pipeline was written by Karly Garnock-Jones of Adis International, using data derived from Adis Clinical Trials Insight and R&D Insight. For further information on Adis services, please contact Camille Scot-Smith on 020 7981 0733

10th December 2007

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